Determining Optimal Dose and Duration of Diuretic Treatment in People With Acute Heart Failure (The DOSE-AHF Study)

• Sponsor: Duke University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00577135
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 308
• Locations: 9
• Arms: 4
• Duration (Months): 24
• Patients Per Site: 34.2
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

Heart failure is a disorder in which the heart does not pump blood adequately. This can lead to several serious problems, including reduced blood flow throughout the body, congestion of blood in the veins and lungs, and fluid accumulation in various organs and limbs. Diuretics are often used to address the problem of fluid accumulation, but the optimal dose and the amount of time over which to administer each dose are unclear. This study will compare high and low doses of diuretics administered over longer and shorter periods of time to determine the safest and most effective combination.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure	Drug: Furosemide-Q12 hour bolus; Drug: Furosemide-Continuous Infusion; Drug: Furosemide-Low Intensification; Drug: Furosemide-High Intensification	Phase 3

Detailed Description

Heart failure is a common disorder in which the heart cannot pump enough blood to meet the needs of the rest of the body. Heart failure symptoms include shortness of breath, swelling, and fatigue. Standard treatment for the swelling associated with heart failure includes the use of diuretic medications, such as furosemide, which cause urination and the removal of excess fluids in the body. Although furosemide has been used to treat heart failure patients for many years, it is still unclear how much of the drug to use, and over what time period the drug should be given. This study will evaluate whether furosemide treatment is safer and more effective when the drug is given in high doses versus low doses and in two to three separate doses versus one continuous infusion.

Participants in this study will begin study procedures within the first 24 hours of their hospital admission for heart failure. Participants will be randomly assigned to receive one of the following four treatments: high dose furosemide via continuous intravenous (IV) infusion and placebo every 12 hours via IV bolus; low dose furosemide via continuous IV infusion and placebo every 12 hours via IV bolus; high dose furosemide every 12 hours via IV bolus and placebo via continuous IV infusion; and low dose furosemide every 12 hours via IV bolus and placebo via continuous IV infusion. Each participant will receive treatment for the first 72 hours of his or her hospital stay. Participants will answer questionnaires and undergo physical examinations and blood tests during the first 96 hours of hospitalization and again before hospital discharge or on Day 7, if that occurs first. Participants will be asked to return to their doctors 60 days following hospital discharge to evaluate their responses to treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 308 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Diuretic Optimal Strategy Evaluation in Acute Heart Failure (The DOSE-AHF Study)
• Study Start Date: Feb 1, 2008
• Actual Primary Completion Date: Jan 1, 2010
• Actual Study Completion Date: Feb 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Q12 hour bolus Furosemide-Q12 hour bolus	Drug: Furosemide-Low Intensification; 1x oral dose; Other Names: Loop diuretic ; Drug: Furosemide-High Intensification; 2.5x oral dose; Other Names: loop diuretic
Experimental: Continuous Infusion Furosemide-Continuous Infusion	Drug: Furosemide-Low Intensification; 1x oral dose; Other Names: Loop diuretic ; Drug: Furosemide-High Intensification; 2.5x oral dose; Other Names: loop diuretic
Experimental: Low Intensification Furosemide-Low Intensification	Drug: Furosemide-Q12 hour bolus; Q12 hours bolus; Other Names: Loop diuretics ; Drug: Furosemide-Continuous Infusion; Continuous infusion; Other Names: Loop diuretic
Experimental: High Intensification Furosemide-High Intensification	Drug: Furosemide-Q12 hour bolus; Q12 hours bolus; Other Names: Loop diuretics ; Drug: Furosemide-Continuous Infusion; Continuous infusion; Other Names: Loop diuretic

Outcome Measures

Primary Outcome Measures

1. Patient Well Being, as Determined by a Visual Analog Scale [Measured at 72 hours]

   Global Visual Analog Scale Scale Range 0-7200; higher score is better

2. Change in Serum Creatinine [Measured at baseline and 72 hours]

Secondary Outcome Measures

1. Change in Weight [baseline and 96 hours]

2. Proportion of Patients Free of Congestion [Measured at 72 hours]

3. Dyspnea, as Determined by Visual Analog Scales [Measured at 24 hours]

   Global Visual Analog Scale Scale Range 0-2400; higher score is better

4. Change in Serum Creatinine [baseline and 24 hours]

5. Change in Cystatin C [baseline and 72 hours]

6. Change in Serum Creatinine [baseline and 48 hours]

7. Change in Serum Creatinine [baseline and 96 hours]

8. Change in Serum Creatinine [baseline and day 7]

9. Change in Serum Creatinine [baseline and day 60]

10. Patient Well Being, as Determined by a Visual Analog Scale [Measured at 24 hours]

    Global Visual Analog Scale Scale Range 0-2400; higher score is better

11. Patient Well Being, as Determined by a Visual Analog Scale [48 hours]

    Global Visual Analog Scale Scale Range 0-4800; higher score is better

12. Dyspnea VAS [48 hours]

    Dyspnea Visual Analog Scale Scale Range 0-4800; higher score is better

13. Dyspnea VAS [72 hours]

    Dyspnea Visual Analog Scale Scale Range 0-7200; higher score is better

14. Change in Cystatin C [baseline and day 7]

15. Change in Cystatin C [baseline and day 60]

16. Change in Uric Acid [baseline and 72 hours]

17. Change in Uric Acid [baseline and day 7]

18. Change in Uric Acid [baseline and Day 60]

19. Change in B-type Natriuretic Peptide [baseline and 72 hours]

    Change in NTproBNP

20. Change in NTproBNP [baseline and Day 7]

21. Change in NTproBNP [baseline and Day 60]

22. Presence of Cardiorenal Syndrome [Within 72 hours]

23. Treatment Failure [Within 72 hours]

    Treatment failure is defined as the patient met cardiorenal syndrome endpoint, worsening or persistent heart failure endpoint, patient died, or there was clinical evidence of overdiuresis requiring intervention within first 72 hours after randomization

24. Net Fluid Loss [Through 24 hours]

25. Net Fluid Loss [Through 48 hours]

26. Net Fluid Loss [Through 72 hours]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Prior clinical diagnosis of heart failure that was treated with daily oral loop diuretics for at least 1 month

• Current diagnosis of heart failure, as defined by the presence of at least 1 symptom (dyspnea, orthopnea, or edema) AND 1 sign (rales on auscultation, peripheral edema, ascites, pulmonary vascular congestion on chest radiography)

• Daily oral dose of furosemide between 80 mg and 240 mg (or equivalent)

• Identified within 24 hours of hospital admission

• Current treatment plan includes IV loop diuretics for at least 48 hours

Exclusion Criteria:

• Brain natriuretic peptide (BNP) less than 250 mg/mL or N-terminal prohormone brain natriuretic peptide (NT-proBNP) less than 1000 mg/mL

• Received IV vasoactive treatment or ultra-filtration therapy for heart failure since initial presentation

• Treatment plan during current hospitalization includes IV vasoactive treatment or ultra-filtration for heart failure

• Substantial diuretic response to pre-randomization diuretic dosing such that higher doses of diuretics would be medically inadvisable

• Systolic blood pressure less than 90 mm Hg

• Serum creatinine level greater than 3.0 mg/dL at baseline or currently undergoing renal replacement therapy

• Hemodynamically significant arrhythmias

• Acute coronary syndrome within 4 weeks prior to study entry

• Active myocarditis

• Hypertrophic obstructive cardiomyopathy

• Severe stenotic valvular disease

• Restrictive or constrictive cardiomyopathy

• Complex congenital heart disease

• Constrictive pericarditis

• Non-cardiac pulmonary edema

• Clinical evidence of digoxin toxicity

• Need for mechanical hemodynamic support

• Sepsis

• Terminal illness (other than heart failure) with expected survival time of less than 1 year

• History of adverse reaction to the study drugs

• Use of IV iodinated radiocontrast material within 72 hours prior to study entry or planned during hospitalization

• Enrollment or planned enrollment in another randomized clinical trial during this hospitalization

• Inability to comply with planned study procedures

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Morehouse School of Medicine	Atlanta	Georgia	United States	30310
2	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
3	Minnesota Heart Failure Network	Minneapolis	Minnesota	United States	55415
4	Mayo Clinic	Rochester	Minnesota	United States	55905
5	Duke University Medical Center	Durham	North Carolina	United States	27705
6	Baylor College of Medicine	Houston	Texas	United States	77030
7	University of Utah Health Sciences Center	Murray	Utah	United States	84107
8	University of Vermont - Fletcher Allen Health Care	Burlington	Vermont	United States	05401
9	Montreal Heart Institute	Montreal	Quebec	Canada	H1T - 1C8

Sponsors and Collaborators

• Duke University
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Kerry L. Lee, PhD, Duke Clinical Research Institute
• Study Chair: Eugene Braunwald, MD, Harvard University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT00577135
• Other Study ID Numbers: Pro00017634; U01HL084904-01
• First Posted: Dec 19, 2007
• Last Update Posted: Mar 6, 2018
• Last Verified: Apr 1, 2013

• Keywords provided by Duke University: Loop Diuretics; Furosemide; Fluid Overload; Cardio Renal Failure
• Additional relevant MeSH terms: Heart Failure; Furosemide; Diuretics; Sodium Potassium Chloride Symporter Inhibitors

Study Results

Participant Flow

Arm/Group Title	Q12 Hours Bolus & Low Intensification	Q12 Hours Bolus & High Intensification	Continuous Infusion & Low Intensification	Continuous Infusion & High Intensification
Arm/Group Description	Low intensification (1 x oral dose) IV furosemide by Q12 hours bolus	High intensification (2.5 x oral dose) IV furosemide by Q12 hours bolus	Low intensification (1 x oral dose) IV furosemide by continuous infusion	High intensification (2.5 x oral dose) IV furosemide by continuous infusion
Period Title: Overall Study
STARTED	74	82	77	75
COMPLETED	74	82	77	75
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Q12 Hours Bolus & Low Intensification	Q12 Hours Bolus & High Intensification	Continuous Infusion & Low Intensification	Continuous Infusion & High Intensification	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	74	82	77	75	308
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.4 (12.4)	65.2 (13.8)	64.5 (14.1)	67.2 (14.0)	66.0 (13.6)
Sex: Female, Male (Count of Participants)
Female	18 24.3%	23 28%	23 29.9%	18 24%	82 26.6%
Male	56 75.7%	59 72%	54 70.1%	57 76%	226 73.4%

Outcome Measures

1. Primary Outcome

Title	Patient Well Being, as Determined by a Visual Analog Scale
Description	Global Visual Analog Scale Scale Range 0-7200; higher score is better
Time Frame	Measured at 72 hours

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	154	149	148	155
Mean (Standard Deviation) [units on a scale]	4236 (1440.4)	4372.7 (1404.4)	4170.8 (1436.3)	4429.6 (1401.4)

2. Primary Outcome

Title	Change in Serum Creatinine
Time Frame	Measured at baseline and 72 hours

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	155	146	147	154
Mean (Standard Deviation) [mg/dL]	0.05 (0.30)	0.07 (0.30)	0.04 (0.29)	0.08 (0.31)

3. Secondary Outcome

Title	Change in Weight
Time Frame	baseline and 96 hours

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	151	142	141	152
Mean (Standard Deviation) [lbs]	-8.0 (7.8)	-9.1 (10.2)	-7.4 (10.1)	-9.6 (7.9)

4. Secondary Outcome

Title	Proportion of Patients Free of Congestion
Time Frame	Measured at 72 hours

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	153	144	143	154
Number [percentage of participants]	14.4 19.5%	15.3 18.7%	11.2 14.5%	18.2 24.3%

5. Secondary Outcome

Title	Dyspnea, as Determined by Visual Analog Scales
Description	Global Visual Analog Scale Scale Range 0-2400; higher score is better
Time Frame	Measured at 24 hours

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	153	149	147	155
Mean (Standard Deviation) [units on a scale]	1370.8 (486.0)	1453.8 (518.0)	1426.0 (504.5)	1398.2 (502.7)

6. Secondary Outcome

Title	Change in Serum Creatinine
Time Frame	baseline and 24 hours

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	154	146	147	153
Mean (Standard Deviation) [mg/dL]	0.00 (0.18)	0.01 (0.17)	-0.01 (0.16)	0.02 (0.19)

7. Secondary Outcome

Title	Change in Cystatin C
Time Frame	baseline and 72 hours

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	125	122	121	126
Mean (Standard Deviation) [mg/L]	0.11 (0.30)	0.17 (0.35)	0.12 (0.35)	0.17 (0.31)

8. Secondary Outcome

Title	Change in Serum Creatinine
Time Frame	baseline and 48 hours

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	155	146	147	154
Mean (Standard Deviation) [mg/dL]	0.02 (0.23)	0.05 (0.26)	0.01 (0.23)	0.06 (0.25)

9. Secondary Outcome

Title	Change in Serum Creatinine
Time Frame	baseline and 96 hours

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	155	146	147	154
Mean (Standard Deviation) [mg/dL]	0.06 (0.32)	0.05 (0.32)	0.05 (0.33)	0.07 (0.31)

10. Secondary Outcome

Title	Change in Serum Creatinine
Time Frame	baseline and day 7

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	155	146	147	154
Mean (Standard Deviation) [mg/dL]	0.10 (0.40)	0.04 (0.32)	0.07 (0.33)	0.08 (0.40)

11. Secondary Outcome

Title	Change in Serum Creatinine
Time Frame	baseline and day 60

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	117	116	114	119
Mean (Standard Deviation) [mg/dL]	0.09 (0.41)	0.07 (0.45)	0.09 (0.43)	0.07 (0.43)

12. Secondary Outcome

Title	Patient Well Being, as Determined by a Visual Analog Scale
Description	Global Visual Analog Scale Scale Range 0-2400; higher score is better
Time Frame	Measured at 24 hours

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	153	149	147	155
Mean (Standard Deviation) [units on a scale]	1280.8 (469.7)	1303.0 (465.1)	1288.6 (455.9)	1294.8 (478.4)

13. Secondary Outcome

Title	Patient Well Being, as Determined by a Visual Analog Scale
Description	Global Visual Analog Scale Scale Range 0-4800; higher score is better
Time Frame	48 hours

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	153	149	147	155
Mean (Standard Deviation) [units on a scale]	2722.6 (940.0)	2792.6 (932.7)	2706.5 (931.5)	2805.2 (939.8)

14. Secondary Outcome

Title	Dyspnea VAS
Description	Dyspnea Visual Analog Scale Scale Range 0-4800; higher score is better
Time Frame	48 hours

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	153	149	147	155
Mean (Standard Deviation) [units on a scale]	2876.6 (960.1)	3033.1 (1039.3)	2924.9 (1012.8)	2981.3 (992.9)

15. Secondary Outcome

Title	Dyspnea VAS
Description	Dyspnea Visual Analog Scale Scale Range 0-7200; higher score is better
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	154	149	148	155
Mean (Standard Deviation) [units on a scale]	4455.6 (1468.4)	4699.1 (1572.7)	4477.9 (1549.7)	4668.3 (1496.0)

16. Secondary Outcome

Title	Change in Cystatin C
Time Frame	baseline and day 7

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	137	131	131	137
Mean (Standard Deviation) [mg/L]	0.21 (0.43)	0.16 (0.48)	0.16 (0.48)	0.21 (0.42)

17. Secondary Outcome

Title	Change in Cystatin C
Time Frame	baseline and day 60

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	92	98	91	99
Mean (Standard Deviation) [mg/L]	0.20 (0.51)	0.16 (0.43)	0.18 (0.47)	0.18 (0.46)

18. Secondary Outcome

Title	Change in Uric Acid
Time Frame	baseline and 72 hours

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	125	121	120	126
Mean (Standard Deviation) [mg/dL]	0.30 (1.02)	0.44 (1.20)	0.11 (1.01)	0.61 (1.15)

19. Secondary Outcome

Title	Change in Uric Acid
Time Frame	baseline and day 7

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	137	130	130	137
Mean (Standard Deviation) [mg/dL]	0.40 (1.47)	0.09 (1.96)	0.07 (1.69)	0.42 (1.75)

20. Secondary Outcome

Title	Change in Uric Acid
Time Frame	baseline and Day 60

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	92	99	93	98
Mean (Standard Deviation) [mg/dL]	-0.09 (2.28)	-0.71 (2.27)	-0.13 (2.33)	-0.67 (2.24)

21. Secondary Outcome

Title	Change in B-type Natriuretic Peptide
Description	Change in NTproBNP
Time Frame	baseline and 72 hours

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	124	121	121	124
Mean (Standard Deviation) [pg/mL]	-1316.2 (4364.3)	-1773.2 (3827.5)	-1193.8 (4094.1)	-1881.6 (4105.4)

22. Secondary Outcome

Title	Change in NTproBNP
Time Frame	baseline and Day 7

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	136	130	131	135
Mean (Standard Deviation) [pg/mL]	-1133.3 (4883.4)	-1552.0 (4875.8)	-1037.2 (5211.8)	-1629.7 (4524.6)

23. Secondary Outcome

Title	Change in NTproBNP
Time Frame	baseline and Day 60

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	91	98	91	98
Mean (Standard Deviation) [pg/mL]	-1449.3 (5010.1)	-1035.1 (6962.9)	-1445.6 (5805.3)	-1038.5 (6364.3)

24. Secondary Outcome

Title	Presence of Cardiorenal Syndrome
Time Frame	Within 72 hours

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	155	146	147	154
Number [percentage of participants]	17.4 23.5%	19.2 23.4%	13.6 17.7%	22.7 30.3%

25. Secondary Outcome

Title	Treatment Failure
Description	Treatment failure is defined as the patient met cardiorenal syndrome endpoint, worsening or persistent heart failure endpoint, patient died, or there was clinical evidence of overdiuresis requiring intervention within first 72 hours after randomization
Time Frame	Within 72 hours

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	155	147	147	155
Number [percentage of participants]	38.1 51.5%	38.8 47.3%	36.7 47.7%	40.0 53.3%

26. Secondary Outcome

Title	Net Fluid Loss
Time Frame	Through 24 hours

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	150	140	141	149
Mean (Standard Deviation) [mL]	1595.7 (1476.7)	1796.4 (1685.1)	1209.7 (1309.3)	2149.6 (1681.7)

27. Secondary Outcome

Title	Net Fluid Loss
Time Frame	Through 48 hours

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	148	136	139	145
Mean (Standard Deviation) [mL]	2996.7 (2490.5)	3120.6 (2504.2)	2334.8 (2006.4)	3747.4 (2716.1)

28. Secondary Outcome

Title	Net Fluid Loss
Time Frame	Through 72 hours

Outcome Measure Data

Analysis Population Description

Each analysis performed for this trial was done twice. The first analysis compared Q12hour versus continuous, the second analysis compared low intensification versus high intensification. The study was not testing the combined 4 way as a pre-specified analysis.

Arm/Group Title	Q 12 Hour Bolus	Continuous Infusion	Low Intensification	High Intensification
Arm/Group Description
Measure Participants	129	113	120	122
Mean (Standard Deviation) [mL]	4236.7 (3207.6)	4249.2 (3104.3)	3575.2 (2634.8)	4898.9 (3478.5)

Adverse Events

Adverse Event Reporting Description	Only Serious Adverse Events were collected for this study
Arm/Group Title	Q 12 Hour Bolus		Continuous Infusion		Low Intensification		High Intensification
Arm/Group Description
All Cause Mortality
	Q 12 Hour Bolus		Continuous Infusion		Low Intensification		High Intensification
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Q 12 Hour Bolus		Continuous Infusion		Low Intensification		High Intensification
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	69/156 (44.2%)		67/152 (44.1%)		76/151 (50.3%)		60/157 (38.2%)
Blood and lymphatic system disorders
Anemia	3/156 (1.9%)		0/152 (0%)		2/151 (1.3%)		1/157 (0.6%)
Cardiac disorders
Cardiac Failure	17/156 (10.9%)		18/152 (11.8%)		20/151 (13.2%)		15/157 (9.6%)
Cardiac Failure Acute	13/156 (8.3%)		6/152 (3.9%)		9/151 (6%)		10/157 (6.4%)
Ventricular Tachycardia	7/156 (4.5%)		4/152 (2.6%)		7/151 (4.6%)		4/157 (2.5%)
Acute Myocardial Infarction	4/156 (2.6%)		1/152 (0.7%)		4/151 (2.6%)		1/157 (0.6%)
Cardiac Arrest	3/156 (1.9%)		3/152 (2%)		3/151 (2%)		3/157 (1.9%)
Angina Pectoris	2/156 (1.3%)		1/152 (0.7%)		2/151 (1.3%)		1/157 (0.6%)
Atrial Fibrillation	1/156 (0.6%)		2/152 (1.3%)		2/151 (1.3%)		1/157 (0.6%)
Atrial Tachycardia	1/156 (0.6%)		1/152 (0.7%)		1/151 (0.7%)		1/157 (0.6%)
Cardiac Failure Chronic	1/156 (0.6%)		3/152 (2%)		2/151 (1.3%)		2/157 (1.3%)
Cardiogenic Shock	1/156 (0.6%)		0/152 (0%)		1/151 (0.7%)		0/157 (0%)
Myocardial Infarction	1/156 (0.6%)		0/152 (0%)		0/151 (0%)		1/157 (0.6%)
Ventricular Arrhythmia	1/156 (0.6%)		1/152 (0.7%)		2/151 (1.3%)		0/157 (0%)
Infections and infestations
Sepsis	3/156 (1.9%)		4/152 (2.6%)		5/151 (3.3%)		2/157 (1.3%)
Metabolism and nutrition disorders
Hyperkalaemia	2/156 (1.3%)		6/152 (3.9%)		3/151 (2%)		5/157 (3.2%)
Nervous system disorders
Cerebrovascular Accident	2/156 (1.3%)		2/152 (1.3%)		3/151 (2%)		1/157 (0.6%)
Renal and urinary disorders
Renal Failure	5/156 (3.2%)		6/152 (3.9%)		7/151 (4.6%)		4/157 (2.5%)
Renal Failure Acute	3/156 (1.9%)		5/152 (3.3%)		6/151 (4%)		2/157 (1.3%)
Renal Failure Chronic	0/156 (0%)		1/152 (0.7%)		0/151 (0%)		1/157 (0.6%)
Vascular disorders
Hypotension	7/156 (4.5%)		9/152 (5.9%)		11/151 (7.3%)		5/157 (3.2%)
Arterial Thrombosis Limb	1/156 (0.6%)		0/152 (0%)		1/151 (0.7%)		0/157 (0%)
Deep Vein Thrombosis	1/156 (0.6%)		0/152 (0%)		1/151 (0.7%)		0/157 (0%)
Shock Haemorrhagic	0/156 (0%)		1/152 (0.7%)		1/151 (0.7%)		0/157 (0%)
Other (Not Including Serious) Adverse Events
	Q 12 Hour Bolus		Continuous Infusion		Low Intensification		High Intensification
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.